During the current reporting period we have focused on two major projects: 1) The genomics of late-stage endometrioid endometrial carcinoma (EC) Endometrioid ECs account for about 80% of newly diagnosed endometrial carcinomas. Most endometrioid ECs are detected at an early clinical stage, when surgery can be curative, but about 15% of cases are detected when they are already at an advanced stage (FIGO stage III or IV) and have metastasized beyond the uterus. Patients with advanced-stage endometrioid tumors have a relatively poor prognosis. The goals of this project are (a) to identify somatically mutated genes in advanced-stage endometrioid ECs and (b) to determine whether any of the mutated genes are enriched in late-stage disease compared to early stage disease. In the previous reporting periods we exome sequenced DNA from 19 late stage primary endometrioid endometrial tumors and matched non-tumor tissues and called somatic (tumor-specific) variant in each tumor. We rigorously filtered and annotated this dataset to delineate high-confidence somatic single nucleotide variants (SNVs). In parallel we performed microsatellite instability testing to distinguish microsatellite stable and microsatellite unstable tumors. In the current reporting period we defined high-confidence insertions and deletions, combined this mutation set with the high-confidence SNV dataset, and then implemented and used MutSigCV to identify statistically significantly mutated genes which are by definition potential driver genes. In ongoing studies, we have shifted our focus to determine whether the significantly mutated genes, and a user-defined set of candidate driver genes, are enriched in late-stage disease compared with early stage disease. 2) The functional annotation of FBXW7 mutations in serous endometrial carcinoma (EC) Serous endometrial carcinomas (ECs) are a particularly aggressive form of endometrial cancer associated with a poor prognosis. In a previous reporting period, we discovered frequent and recurrent somatic mutations in the FBXW7 gene in endometrial carcinomas, particularly in the serous and clear cell subtypes (Nature Genetics 2012; 44:1310-5). We thus hypothesized that FBXW7 mutations, particularly recurrent mutations in exons encoding the WD-repeats of the FBXW7 protein, are deleterious mutations that disrupt the proper function of the FBXW7 protein. In the current reporting period we concluded a long-term study designed to test this hypothesis, which uncovered key functional consequences of FBXW7 mutations in EC and provided in vitro evidence for an association between FBXW7 mutations and sensitivity to targeted inhibitors in a serous EC cell line. We recently published a manuscript describing our findings (Urick and Bell, Molecular Carcinogenesis, 2018: doi: 10.1002/mc.22867).